The cellular basis of alcohol action in the nervous system is poorly understood. Alcohols can affect the function of neurotransmitter receptors; however, the mechanisms have not been established. We used patch-clamp recording to study the cellular mechanisms of alcohol action on these receptors. Some laboratories have reported that GABAa receptors are sensitive to pharmacologic concentrations of ethanol (5- 100 mM), whereas others have reported that they are not. It has been proposed that the reason for these divergent observations is that PKC- induced phosphorylation of the gamma-2-L subunit is required for the receptor to be sensitive to ethanol. We studied this hypothesis in rat dorsal root ganglion neurons. The presence of the gamma-2-L subunit mRNA was confirmed using RT-PCR. GABA responses remained insensitive to ethanol concentrations from 2.5-100 mM despite: (i) extracellular phorbol ester; (ii) raising intracellular Ca2+; (iii) intracellular PKC; and (iv) extracellular phorbol ester plus intracellular protein phosphatase inhibitors. The observations do not support the hypothesis that PKC phosphorylation of gamma-2-L induces ethanol sensitivity of GABAa receptors. We also studied the alcohol sensitivity of GABAa receptors in mouse hippocampal neurons. N-alcohols from ethanol to dodecanol enhanced GABA responses, whereas higher alcohols had no effect. The EC50 for ethanol was 2160 mM. The n-alcohol potency curve for enhancement of GABAa receptor function was similar to the n-alcohol potency curve for anesthesia in tadpoles. In addition, the anesthetic potency of n-alcohols in rats more closely reflected NMDA receptor modulatory potency for lower alcohols and GABAa receptor modulatory potency for higher alcohols. - neuroscience, alcohol, neuron, synapse, receptor, ion channel, electrophysiology